This application claims priority to PCT Appl. No. PCT/GB92/01697, filed Sep. 16, 1992, which claims priority to Great Britain Appl. No. 9120306.7, filed Sep. 24, 1991.
The present invention relates to the treatment of cerebral palsy in a juvenile patient and in particular to the promotion of normal muscle growth in a juvenile patient suffering from dynamic contractures caused by cerebral palsy.
Cerebral palsy is a collective name given to a range of conditions caused by brain injury caused at or around the time of birth, or in the first year of an infant""s life. The brain injury may be caused, for example, by trauma during delivery. It may also arise through such causes as trauma due to road traffic accidents or meningitis during the first year of life. It has been found that there is an increased risk of cerebral palsy in prematurely born babies and, as a result of the improvements in technology which enable premature babies to be kept alive from a much earlier age, the incidence of cerebral palsy in many countries is actually increasing rather than falling.
Although the brain injury causing cerebral palsy is a non-progressive injury, its effects may change as the sufferer grows older. The largest group of sufferers from cerebral palsy suffer from spastic cerebral palsy. Spastic cerebral palsy is characterised by dynamic contractures of the muscles which impair or inhibit completely the sufferer""s ability to use his or her muscles. Moreover, muscle growth is impaired such that the longitudinal muscles become shorter relative to their associated bones as the infant grows older. Where the leg muscles are affected, the mobility of the sufferer can be severely reduced. Conventional attempts to cure this defect and to restore a measure of normal mobility typically have involved surgical intervention to alter the lengths of the tendons once the stage has been reached at which the knee joint can no longer be straightened or the sufferer can only walk on tiptoe.
There remains a need for a treatment which allows the longitudinal muscles to grow normally, thereby removing, or at least minimising the need to resort to surgical intervention. Moreover, there remains a need for a treatment which can augment surgical intervention to improve the mobility of the sufferer.
A bacterial toxin, botulinum toxin, has been used in the treatment of a number of conditions involving muscular spasm, for example blepharospasm, spasmodic torticollis (cervical dystonia), oromandibular dystonia and spasmodic dysphonia (laryngeal dystonia). The toxin binds rapidly and strongly to presynaptic cholinergic nerve terminals and inhibits the exocytosis of acetylcholine by decreasing the frequency of acetyl choline release. This results in paralysis, and hence relaxation, of the muscle afflicted by spasm.
The term Botulinum toxin as used herein is a generic term embracing the family of toxins produced by the anaerobic bacterium Clostridium botulinum and, to date, seven immunologically distinct toxins have been identified. These have been given the designations A, B, C, D, E, F and G. For further information concerning the properties of the various botulinum toxins, reference is made to the article by Jankovic and Brin, The New England Journal of Medicine, pp 1186-1194, No 17, 1991 and to the review by Charles L Hatheway, Chapter 1 of the book entitled Botulinum Neurotoxin and Tetanus Toxin Ed. L. L. Simpson, published by Academic Press Inc. of San Diego Calif. 1989, the disclosures in which are incorporated herein by reference.
The neurotoxic component of botulinum toxin has a molecular weight of about 150 kilodaltons and is thought to comprise a short polypeptide chain of about 50 kD which is considered to be responsible for the toxic properties of the toxin, and a larger polypeptide chain of about 100 kD which is believed to be necessary to enable the toxin to penetrate the nerve. The xe2x80x9cshortxe2x80x9d and xe2x80x9clongxe2x80x9d chains are linked together by means of disulphide bridges.
The neurotoxic polypeptide component is present in a complex with non-toxic proteins and haemagglutinins, the molecular weight of the complex being in the region of 900 kD.
Botulinum toxin is obtained commercially by establishing and growing cultures of C. botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance with known techniques.
The xe2x80x9cAxe2x80x9d form of botulinum toxin is currently available commercially from several sources, for example from Porton Products Ltd UK under the tradename xe2x80x9cDYSPORTxe2x80x9d(copyright), and from Allergan Inc, Irvine, Calif. under the trade name xe2x80x9cOCULINUMxe2x80x9d(copyright).
It has now been found by the present inventor that children suffering from cerebral palsy related dynamic muscle contractures exhibit improvements in function following treatment with botulinum toxin and that such functional improvements persist when the tone reducing effects of the toxin have worn off.
It has also been found that by administering botulinum toxin to a juvenile spastic mammal during its growth phase, the consequent reduction in tone of the spastic muscle enables increased longitudinal growth of the muscle to take place.
In a first aspect, the present invention provides a method of treating a juvenile patient suffering from arrested muscle growth arising from the presence of dynamic contractures of the muscle, which method comprises administering to the patient a therapeutically effective amount of a substance which blocks the release of synaptic vesicles containing acetylcholine.
The present invention also provides a method of treating a juvenile patient suffering from cerebral palsy, which method comprises administering to the patient a therapeutically effective amount of a substance which blocks the release of synaptic vesicles containing acetylcholine.
In a further aspect the invention provides a method of treating a juvenile patient suffering from arrested muscle growth arising from the presence of dynamic contractures of the muscle, which method comprises administering to the patient a therapeutically effective amount of a presynaptic neurotoxin, for example a bacterial neurotoxin such as botulinum toxin.
In a still further aspect the invention provides a method of treating a juvenile patient suffering from arrested muscle growth due to cerebral palsy, which method comprises administering a presynaptic neurotoxin (for example a bacterial neurotoxin such as botulinum toxin) to the patient in a non toxic amount sufficient to reduce muscle tone and promote improved muscle growth.
The botulinum toxin used according to the present invention preferably is Botulinum toxin A. Botulinum toxin A is available commercially from Porton Products Limited, UK, and from Allergan Inc, Irvine, Calif.
Administration of the toxin preferably is by means of intramuscular injection directly into a spastic muscle, in the region of the neuromuscular junction, although alternative types of administration (e.g. sub-cutaneous injection) which can deliver the toxin directly to the affected muscle region may be employed where appropriate. The toxin can be presented as a sterile pyrogen-free aqueous solution or dispersion and as a sterile powder for reconstitution into a sterile solution or dispersion.
Where desired, tonicity adjusting agents such as sodium chloride, glycerol and various sugars can be added. Stabilisers such as human serum albumin may also be included. The formulation may be preserved by means of a suitable pharmaceutically acceptable preservative such as a paraben, although preferably it is unpreserved.
It is preferred that the toxin is formulated in unit dosage form, for example it can be provided as a sterile solution in a vial, or as a vial or sachet containing a lyophilised powder for reconstituting a suitable carrier such as water for injection.
In one embodiment the toxin, e.g. botulinum toxin A is formulated in a solution containing saline and pasteurised human serum albumin, which stabilises the toxin. The solution is sterile filtered (0.2 micron filter), filled into individual vials and then vacuum dried to give a sterile lyophilised powder. In use, the powder can be reconstituted by the addition of sterile unpreserved normal saline (sodium chloride 0.9% for injection).
In order for the benefits of the invention to be realised, administration of the botulinum toxin should commence before the child has completed its growing period and fixed myostatic contracture has occurred. The benefits of the invention can be maximised by administering the botulinum toxin to the child at an early stage in its growing period, for example before the child reaches the age of six.
The dose of toxin administered to the patient will depend upon the severity of the condition e.g. the number of muscle groups requiring treatment, the age and size of the patient and the potency of the toxin. The potency of the toxin is expressed as a multiple of the LD50 value for the mouse, one xe2x80x9cunitxe2x80x9d of toxin being defined as being the equivalent amount of toxin that kills 50% of a group of mice. The definition of potency as used hereinafter is the definition currently used in relation to the product marketed by Porton Products Limited. According to this definition, the potency of the botulinum toxin A available from Porton Products Ltd is such that one nanogram contains 40 mouse units (units).
Typically, the dose administered to the patient will be up to about 1000 units, for example up to about 500 units, and preferably in the range from about 80 to about 460 units per patient per treatment, although smaller or larger doses may be administered in appropriate circumstances. The potency of botulinum toxin, and its long duration of action, means that doses will tend to be administered on an infrequent basis. Ultimately, however, both the quantity of toxin administered, and the frequency of its administration will be at the discretion of the physician responsible for the treatment, and will be commensurate with questions of safety and the effects produced by the toxin.
The invention will now be illustrated in greater detail by reference to the following non-limiting examples which describe the results of clinical studies with botulinum toxin A: